The development of autoimmunity is caused, in part by a failure of negative regulatory mechanisms which ordinarily prevent these diseases from occurring in non-susceptible individuals. Regulation is imposed by anti-inflammatory cytokines which mediate their action, at least in part through regulatory T cells. TGF-beta is, arguably the most important regulatory cytokine which acts at least in part through regulatory CD4+CD25+FoxP3+ positive T cells, and in part through control of other cell types. In this proposal, we will investigate how signaling of TGF-beta into autoaggressive and other T cells prevents the development of T1D, and how this regulation fails in the autoimmune susceptible NOD mouse. Second, we will determine the cellular origin of the TGF-beta which inhibits T1D development. It has been recently shown that anti-CD3 treatment is therapeutic in reversing T1D in humans that have recently developed Type 1 Diabetes. We will determine whether TGF-beta is instrumental in this process and we will elucidate the mechanism whereby this occurs.